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Be aware that cognitive performance was not the subject of this study.

A gene therapy that boosts nerve growth factor (NGF) production in cholinergic neurons was safe and appeared to promote neuronal growth in a small study of patients with early Alzheimer's disease, researchers reported.

All 10 patients in the trial -- which started in 2001 -- showed a trophic response to the growth factor delivered via gene therapy, Mark Tuszynski, MD, PhD, of the University of California San Diego and the San Diego Veterans Affairs clinic, and colleagues reported online in JAMA Neurology.

"In every case, all cholinergic neurons showed growth," Tuszynski told MedPage Today. "We consistently achieved [growth] in every patient who had the procedure."

Tuszynski's group appears to be doing the only gene therapy for Alzheimer's disease. Most therapeutic efforts in the field have focused on the accumulation of amyloid in the brain, but after several failed trials of antibodies targeting accumulation of that protein, researchers have begun to ask whether it's time to explore other therapeutic targets.

NGF gene therapy instead attempts to directly target the neurodegeneration that manifests clinical symptoms. It does not target amyloid.

Tuszynski said his group chose NGF because it stimulates the cholinergic neurons that are impaired so early on in the Alzheimer's disease process. The protein helps to prevent cell death and neurodegeneration.

But why gene therapy instead of just delivering NGF? It's important to keep potent growth factors under control to thwart potential side effects, Tuszynski said.

"It's a better way to go [since] it's simple, efficient, and now we know it's safe," he told MedPage Today, adding that it's also a matter of convenience. "In theory, you could give it once in a person's lifetime and be done. They won't have to take medications."

For their trial, the researchers enrolled 10 patients with early Alzheimer's in what was the first attempt at gene delivery to slow neurodegeneration.

The first eight patients had ex vivo gene therapy, which involves inserting NGF genes into skin fibroblasts and implanting those altered cells into the brain. The final two patients had in vivo gene therapy, in which an adeno-associated viral vector serotype 2 (AAV2) carrying NGF genes were injected into the brain.

The researchers autopsied all 10 brains after patients died. They found that the neurons responded to the therapy in all patients, as evidenced by axonal sprouting toward the NGF source, neuronal hypertrophy, and activation of cell signaling.

Although there are concerns about systemic effects of growth factors in the body, the researchers reported no serious adverse events.

"This is the largest opportunity to date to show that at an anatomical level, [gene therapy delivering NGF] is safe," Tuszynski said. "Growth factors are very potent in the nervous system, and if they're broadly distributed, they can cause off-target adverse effects. But we saw none in these 10 patients."

One patient survived 7 years, and there was evidence that the implanted NGF genes continued to be expressed at that time, he added.

Some researchers not involved in the study told MedPage Today that the data provide encouraging support for the potential of gene therapies that deliver growth factors, but that large clinical trials are needed to see whether this therapy has a meaningful clinical effect.

Others were quick to applaud the work for moving beyond amyloid and into other targets that likely play a role in the Alzheimer's disease process.

"The cholinergic basal forebrain appears to be one of the earliest tangled areas, and [neurofibrillary] tangling may index oxidative stress, inflammation, mitochondrial decline, and perhaps other metabolically undesirable aspects of aging that are being accelerated in the Alzheimer's brain," Douglas Watt, PhD, of the Alzheimer's center at Quincy Medical Center in Boston who was not involved in the study, told MedPage Today.

"From this perspective, it does make sense that nerve growth factor may counter-balance whatever is going on to create early tangling in these cholinergic regions," Watt said.

He added that the "clear implication" of the research is that researchers "really shouldn't be looking at treatments in isolation but in combination."

That includes "anti-inflammatory, pro-plasticity, mitigating sex steroid declines, promoting insulin sensitivity in the brain, correcting circadian imbalances, promoting better mitochondrial function, proving dietary patterns, improving aerobic fitness, reducing social stress and social isolation, etc.," Watt said. "And yet we've had decades of applying single factor therapies in relationship to Alzheimer's disease -- and the vast majority of these have shown minimal to no benefit at all."

Tuszynski noted that a phase 2 multicenter randomized sham-surgery-controlled trial of AAV2-NGF gene delivery is completed and will publish soon.

He and his group also published work on gene therapy with brain-derived neurotrophic factor (BDNF) targeting cortical neurons in animal models in Nature Medicine in 2009, and they are now slated to start human clinical trials in 12 to 18 months, he added.

Tuszynski is the founder of Ceregene but has no present financial interest in the company.

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